We hypothesize that maternal insulin resistance (obesity) influences fetal and/or early postnatal development of hypothalamus to promote obesity and type 2 diabetes (T2DM) in progeny. Such an effect could contribute to the accelerating incidence of obesity and T2DM currently being encountered worldwide. We will develop a mouse model to investigate this issue using genetically imposed maternal insulin resistance as a surrogate for obesity. In preliminary studies, we find that maternal insulin resistance affects adiposity and insulin homeostasis in progeny. The Specific Aims of this project are: 1) to use this mouse model to assess effects of maternal insulin resistance- and interactions with maternal high fat diet- on body composition and energy and insulin homeostasis of progeny; and 2) to examine the molecular/developmental mechanisms through which such maternal insulin resistance influences the development of hypothalamic feeding circuits. We will perform a comprehensive analysis of the consequences of maternal insulin resistance on energy and insulin homeostasis in the progeny and extend the analysis of our model to consider the effects of fat content of the maternal diet. We will assess the effects of maternal insulin resistance on developmental processes in the hypothalamus, initially focusing on the arcuate nucleus. The effects of maternal insulin resistance on the development of the arcuate nucleus will be assessed by quantitative analyses of the cell bodies of three functionally distinct arcuate neuronal populations (POMC, NPY and RIP neurons) and their axonal projections to secondary targets in the hypothalamus. Defining the time window and mechanisms of susceptibility to gestational and early extrauterine effects on the progeny of maternal insulin resistance should provide important insights into the corresponding window of susceptibility in humans. In the longer term, defining the relevant maternal signals influencing molecular events in the developing brain could lead to the design of novel strategies for prevention of obesity/T2DM in humans.